Process For The Preparation Of A Diarylthiohydantoin Compound

ABSTRACT

Disclosed are processes and intermediates for the preparation of compound (X), which is currently being investigated for the treatment of prostate cancer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/427,637, filed May 31, 2019, which is a continuation of U.S. patentapplication Ser. No. 15/537,859, filed Jun. 19, 2017, which is the U.S.national stage of International Patent Application No.PCT/US2015/066345, filed Dec. 17, 2015, which claims priority to U.S.Provisional Patent Application No. 62/094,425, filed Dec. 19, 2014, alldisclosures of which are hereby incorporated by reference in theirentireties.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

The research and development of the invention described below was notfederally sponsored.

FIELD OF THE INVENTION

The present invention is directed to the preparation of compound (X) andintermediates in its synthesis. More specifically, the present inventionis directed to processes for the preparation of compound (X), disclosedin U.S. Pat. No. 8,445,507, issued on May 21, 2013, which is herebyincorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

Compound (X) of the present invention is currently being investigatedfor use in the treatment of prostate cancer. The present inventiondescribes processes and intermediates for the preparation of suchcompound.

SUMMARY OF THE INVENTION

The present invention is directed to a process for the preparation ofcompound (X)

Comprising, consisting of, and/or consisting essentially of

reacting compound (V) with cyclobutanone in the presence of sodiumcyanide; in a solvent such as acetic acid, or a solvent systemcomprised, consisting, or consisting essentially of an alcoholic solventand a protic acid; at a temperature of about 0° C. to about 20° C.; toyield the corresponding compound (VI);

reacting compound (IV) and compound (VI) in the presence of athiocarbonylating agent; in an organic solvent; at a temperature ofabout 0° C. to about 100° C.; to yield the corresponding compound (VII);

converting compound (VII) to compound (X), discussed in further detailbelow.

In one embodiment, compound (VII) is converted to compound (X) via itscorresponding carboxylic acid (1c), as shown in scheme (1c), by

(i) reacting compound (VII) with an organomagnesium halide; in thepresence or absence of a lithium halide; followed by the addition ofcarbon dioxide gas; in an aprotic organic solvent; at a temperature ofabout 0° C.; to yield the corresponding carboxylic acid compound (1c);or,

(ii) reacting compound (VII) under a carbon monoxide atmosphere; in thepresence of a palladium catalyst; in the presence of one or morephosphorus ligands; in the presence of an organic base; in a thepresence of water; in an organic solvent; at a temperature of about 0°C. to about 100° C.; to yield the corresponding compound (1c); then,

reacting compound (1c) with a coupling agent; in an aprotic or proticsolvent; at about room temperature; followed by the addition ofmethylamine; to yield the corresponding compound (X).

In another embodiment, compound (VII) is converted to compound (X) viaits corresponding C₁₋₆alkyl ester (1e), as shown in scheme (1e), by

(i) reacting compound (VII) with an organomagnesium halide; in thepresence or absence of a lithium halide; in an aprotic organic solvent;at a temperature of about −50° C. to about room temperature; followed bythe addition of an C₁₋₆alkyl chloroformate or C₁₋₆alkyl cyanoformate; toyield the corresponding ester of formula (1e); or

(ii) reacting compound (VII) under suitable alkoxycarbonylationconditions; under a carbon monoxide atmosphere; in the presence of apalladium catalyst; in the presence of one or more phosphorus ligands;in the presence of a base; in a C₁₋₆alcoholic solvent; at a temperatureof about room temperature to about 100° C.; to yield the correspondingcompound of formula (1e); then

treating a compound of formula (1e) with methylamine; in a protic oraprotic solvent; at a temperature of about 0° C. to about 60° C.; toyield the corresponding compound (X).

In another embodiment, compound (VII) is converted directly to compound(X), as shown in scheme (1g), by

(i) reacting compound (VII) in the presence of molybdenum hexacarbonyl;optionally in the presence of one or more reagents such asnorbornadiene, tetrabutylammonium bromide, or a base selected fromtriethylamine or DABCO; in an organic solvent; followed by the additionof methylamine; at a temperature of about 60° C. to about 140° C.; toyield the corresponding compound (X); or,

(ii) reacting compound (VII) under suitable aminocarbonylationconditions; under a carbon monoxide atmosphere; in the presence of apalladium catalyst; in the presence of one or more phosphorus ligands;in the presence of a base; in the presence of methylamine; in an organicsolvent; at a temperature of about room temperature to about 100° C.; toyield the corresponding compound (X).

DETAILED DESCRIPTION OF THE INVENTION

The term “alkyl” whether used alone or as part of a substituent group,refers to straight and branched carbon chains having 1 to 8 carbonatoms. Therefore, designated numbers of carbon atoms (e.g., C₁₋₈) referindependently to the number of carbon atoms in an alkyl moiety or to thealkyl portion of a larger alkyl-containing substituent. In substituentgroups with multiple alkyl groups such as, (C₁₋₆alkyl)₂amino-, the C₁₋₆alkyl groups of the dialkylamino may be the same or different.

The term “alkoxy” refers to an —O-alkyl group, wherein the term “alkyl”is as defined above.

The term “cycloalkyl” refers to a saturated or partially saturated,monocyclic hydrocarbon ring of 3 to 8 carbon atoms. Examples of suchrings include cyclopropyl, cyclobutyl, cycloheptyl, cyclohexyl, andcycloheptyl.

The term “aryl” refers to an unsaturated, aromatic monocyclic orbicyclic ring of 6 to 10 carbon members. Examples of aryl rings includephenyl and naphthalenyl.

The term “halogen”, “halide”, or “halo” refers to fluorine, chlorine,bromine and iodine atoms.

The term “carboxy” refers to the group —C(═O)OH.

The term “formyl” refers to the group —C(═O)H.

The term “oxo” or “oxido” refers to the group (═O).

Whenever the term “alkyl” or “aryl” or either of their prefix rootsappear in a name of a substituent (e.g., arylalkyl, alkylamino) the nameis to be interpreted as including those limitations given above for“alkyl” and “aryl.” Designated numbers of carbon atoms (e.g., C₁-C₆)refer independently to the number of carbon atoms in an alkyl moiety, anaryl moiety, or in the alkyl portion of a larger substituent in whichalkyl appears as its prefix root. For alkyl and alkoxy substituents, thedesignated number of carbon atoms includes all of the independentmembers included within a given range specified. For example C₁₋₆ alkylwould include methyl, ethyl, propyl, butyl, pentyl and hexylindividually as well as sub-combinations thereof (e.g., C₁₋₂, C₁₋₃,C₁₋₄, C₁₋₅, C₂₋₆, C₃₋₆, C₄₋₆, C₅₋₆, C₂₋₅, etc.).

In general, under standard nomenclature rules used throughout thisdisclosure, the terminal portion of the designated side chain isdescribed first followed by the adjacent functionality toward the pointof attachment. Thus, for example, a “C₁-C₆ alkylcarbonyl” substituentrefers to a group of the formula:

The term “room temperature” or “ambient temperature”, as used hereinrefers to a temperature in the range of from about 18° C. to about 22°C.

Abbreviations used in the instant specification, particularly theschemes and examples, are as follows:

Abbreviations

-   aq aqueous-   BA [1,1′-biphenyl]-2-amine-   Boc tert-butoxycarbonyl-   CDI 1,1′-carbonyldiimidazole-   CPME cyclopentyl methylether-   Cy cyclohexyl-   DABCO 1,4-diazabicyclo[2.2.2]octane-   DCM dichloromethane-   DIEA or DIPEA diisopropylethylamine-   DMA dimethylacetamide

Abbreviations

-   DMF dimethylformamide-   DMSO methyl sulfoxide-   dppf 1,1′-bis(diphenylphosphino)ferrocine-   h hour(s)-   HCl hydrochloric acid-   HPLC high performance liquid chromatography-   Me methyl-   MeCN acetonitrile-   MeOH methyl alcohol-   mg milligram-   MTBE methyl tert-butylether-   NMP N-methyl-2-pyrrolidone-   PdCl₂(dppf).CH₂Cl₂ 1,1′-bis(di    phenylphosphino)ferrocene-palladium(II)dichloride dichloromethane    complex)-   P(o-tol)₃ tri(o-tolyl)phosphine-   rt room temperature-   THF tetrahydrofuran-   2-MeTHF 2-methyl tetrahydrofuran

General Schemes

The overall scheme for the present invention is illustrated in Scheme A,shown below.

In Scheme A, a compound (V) may be reacted with cyclobutanone and atleast one molar equivalent of sodium cyanide; in a solvent such asacetic acid, or in a solvent system comprised, consisting, or consistingessentially of of at least one molar equivalent of an acid such asacetic acid or hydrochloric acid and a C₁₋₄alcoholic solvent such asmethanol, ethanol, propanol, or butanol; at a temperature of about 0° C.to about 20° C.; to yield the corresponding compound (VI).

In one embodiment, the solvent is acetic acid.

In another embodiment, the solvent system is 90% acetic acid and 10%ethanol.

Compound (IV) may be reacted with a compound of formula (VI) in thepresence of a thiocarbonylating agent selected from1-(2-oxopyridine-1-carbothioyl)pyridin-2-one, 1,1′-thiocarbonyldiimidazole, phenylthionochloroformate, beta-naphthylthionochloroformate, 1,1′-thiocarbonylbis(pyridin-2(1H)-one),O,O-di(pyridin-2-yl)carbonothioate, 1,1′-thiocarbonylbis(1H-benzotriazole), or thiophosgene; in an organic solvent such as THF,2-methyl-THF, acetonitrile, DMA, toluene, DMF, NMP, DMSO, or the like;at a temperature of about 0° C. to about 100° C.; to yield thecorresponding compound (VII).

In one embodiment, the thiocarbonylating agent is1-(2-oxopyridine-1-carbothioyl)pyridin-2-one.

In another embodiment, the organic solvent is DMA.

Conversion to Compound (X) via Carboxylic Acid (1c)

(i) Compound (VII) may be converted to compound (X) via itscorresponding carboxylic acid, compound (1c), by reacting compound (VII)with an organomagnesium halide selected from C₁₋₈alkylmagnesium halideor C₅₋₇cycloalkylmagnesium halide; in the presence or absence of alithium halide such as lithium chloride, lithium bromide, or lithiumiodide; followed by the addition of carbon dioxide gas; in an aproticorganic solvent selected from THF, 2-MeTHF, MTBE, CPME, or toluene; at atemperature of about 0° C.; to yield the corresponding carboxylic acidcompound (1c).

More particularly, the C₁₋₈alkylmagnesium halide is a C₁₋₈alkylmagnesiumchloride or C₁₋₈alkylmagnesium bromide, and the C₅₋₇cycloalkylmagnesiumhalide is a C₅₋₇cycloalkylmagnesium chloride or C₅₋₇ cycloalkylmagnesiumbromide.

In one embodiment, the C₁₋₈alkylmagnesium halide is selected fromisopropylmagnesium chloride, sec-butylmagnesium chloride,n-pentylmagnesium chloride, hexylmagnesium chloride, ethylmagnesiumchloride, ethylmagnesium bromide, n-butylmagnesium chloride, orisopropylmagnesium chloride.

In a further embodiment, the C₁₋₈alkylmagnesium halide isn-pentylmagnesium chloride; and the aprotic organic solvent is THF.

In a further embodiment, a lithium halide is absent.

In another embodiment, the C₅₋₇cycloalkylmagnesium halide iscyclohexylmagnesium chloride.

(ii) Alternatively, compound (VII) may be reacted under a carbonmonoxide atmosphere, in the presence of a palladium catalyst; in thepresence of one or more phosphorus ligands; in the presence of water; ina solvent such as methanol, ethanol, or the like; at a temperature ofabout 0° C. to about 100° C.; to yield the corresponding compound (1c).

It has been found that a variety of palladium catalysts and phosphorusligands are suitable for this transformation. In an embodiment, thepalladium catalyst is either a pre-formed palladium catalyst or apalladium-ligand catalyst complex that is formed in situ. When thepalladium catalyst is a pre-formed palladium catalyst, it is selectedfrom CAT1 to CAT5, shown in Table 1; and may be used for theabove-described preparation of compound (1c).

TABLE 1 Pre-formed Palladium Catalysts Catalyst No. Catalyst NameStructure CAT1 Pd(OMs)(BA) (P(tBu₂-4- N,N- dimethyl- aniline))

CAT2 Pd(OMs)(BA) (P(tBu₂- neopentyl)

CAT3 Pd(P(tBu₃)₂

CAT4 [Pd(OAc) (P(o-Tol)₃]₂

CAT5 [PdCl₂(L3)] = PCl₂(dppf)

In another embodiment, one or more phosphorus ligands selected from L1to L17, shown in Table 2, may be used in combination with either apre-formed palladium catalyst (Table 1) or a palladium metal compound(Table 3), for the preparation of compound (1c).

TABLE 2 Phosphorus Ligands Ligand No. Structure L1

L2

L3

L4

L5

L6

L7

L8

L9

L10

L11

L12

L13

L14

L15

L16

L17

In another embodiment, a palladium metal compound selected from M1 toM2, shown in Table 3 may be used.

TABLE 3 Palladium Metal Compounds Metal Metal No. Cpd Name Structure M1palladium acetate

M2 [Pd(OMs)(BA)]₂

In an embodiment, the palladium catalyst is comprised, consisting, orconsisting essentially of the phosphorus ligand dppf (L1 Table 2) andthe palladium metal compound palladium acetate (M1, Table 3).

Compound (1c) may then be treated with a coupling agent such as CM; inan aprotic or protic solvent such as THF, toluene, or the like; at aboutroom temperature; followed by the addition of methylamine; to yield thecorresponding compound (X).

In one embodiment, methylamine is added as a solution in a protic oraprotic solvent. In a further embodiment, methylamine is added as a THFsolution.

In another embodiment, methylamine is added in its gaseous state.

In yet another embodiment, methylamine is added as its methyl ammoniumsalt.

Conversion to Compound (X) Via Ester (1e)

(i) Compound (VII) may also be converted to compound (X) via itscorresponding C₁₋₆alkyl ester (1e), by reacting compound (VII) with anorganomagnesium halide selected from a C₁₋₈alkylmagnesium halide or aC₅₋₇cycloalkylmagnesium halide; in the presence or absence of a lithiumhalide such as lithium chloride, lithium bromide, or lithium iodide; inan aprotic organic solvent selected from THF, 2-MeTHF, toluene, or thelike; at a temperature of about −50° C. to about 22° C.; followed by theaddition of a C₁₋₆ alkyl chloroformate or C₁₋₆alkyl cyanoformate; toyield the corresponding ester of formula (1e).

More particularly, the C₁₋₈alkylmagnesium halide is a C₁₋₈alkylmagnesiumchloride or C₁₋₈alkylmagnesium bromide, and the C₅₋₇cycloalkylmagnesiumhalide is a C₅₋₇cycloalkylmagnesium chloride or C₅₋₇cycloalkylmagnesiumbromide.

In one embodiment, the C₁₋₈alkylmagnesium halide is selected fromisopropylmagnesium chloride, sec-butylmagnesium chloride,cyclohexylmagnesium chloride, n-pentylmagnesium chloride, hexylmagnesiumchloride, ethylmagnesium chloride, ethylmagnesium bromide,n-butylmagnesium chloride; or isopropylmagnesium chloride.

In another embodiment, the C₁₋₈alkylmagnesium halide isn-pentylmagnesium chloride and the aprotic organic solvent is THF or2-MeTHF.

In a further embodiment, a lithium halide is absent.

(ii) Alternatively, compound (VII) may be reacted under suitablealkoxycarbonylation conditions, under a carbon monoxide atmosphere; inthe presence of a palladium catalyst; in the presence of one or morephosphorus ligands; with a base such as DIPEA, K₂CO₃, K₃PO₄, or Cy₂NMe;in a C₁₋₄alcoholic solvent selected from methanol, ethanol, isopropylalcohol, n-butyl alcohol, or t-butyl alcohol; to yield the correspondingcompound of formula (1e).

It has been found that a variety of palladium catalysts and phosphorusligands are suitable for this transformation. In an embodiment, thepalladium catalyst is either a pre-formed palladium catalyst or apalladium-ligand catalyst complex that is formed in situ. When thepalladium catalyst is a pre-formed palladium catalyst, it is selectedfrom CAT1 to CAT5, shown in Table 1 (above), and may be used for thepreparation of a compound of formula (1e).

In another embodiment, one or more phosphorus ligands selected from L1to L17, shown in Table 2 (above), may be used in combination with eithera pre-formed palladium catalyst (Table 1) or a palladium metal compound(Table 3), for the preparation of a compound of formula (1e).

In another embodiment, a palladium metal compound selected from M1 or M2(Table 3, above) may be used, in combination with one or more phosphorusligands selected from L1 to L17 from Table 2, for the above-describedalkoxycarbonylation reaction.

Table 4 describes certain reaction conditions (E1 to E8) for theconversion of compound (VII) to methyl ester (1e-1), wherein C₁₋₆ alkylof a compound of formula (1e) is methyl.

TABLE 4 Conditions for Alkoxycarbonylation of Compound (VII) to MethylEster (1e−1) Metal/Cat. Ligand Base Conv. (%) Yield (%) E1 Pd(P(tBu₃)₂ —DIPEA 100.0 82.1 E2 [Pd(OMs)BA)]₂ L10 Cy₂NMe 99.0 72.5 E3 PdCl₂dppf —Cy₂NMe 98.8 81.7 E4 PdCl₂dppf — DIPEA 98.7 84.8 E5 [Pd(OMs)BA)]₂ L17Cy₂NMe 98.4 83.8 E6 [Pd(OMs)BA)]₂ L13 Cy₂NMe 92.0 72.8 E7 Pd(OAc)₂ L10Cy₂NMe 84.0 75.4 E8 Pd(OAc)₂ L16 Cy₂NMe 78.8 73.0

In an embodiment, the process for the conversion of compound (VII) to acompound of formula (1e) is in the presence of the palladium catalystPd(P(iBu₃)₂ (CAT3, Table 1), and 1.2 equivalents of DIPEA.

In another embodiment, the palladium catalyst is comprised, consisting,consisting essentially of the phosphorus ligand L10 (Table 2) and thepalladium metal compound [Pd(OMs)(BA)]₂ (M2, Table 3). In anotherembodiment, the organic base is Cy₂NMe.

In another embodiment, the palladium catalyst is comprised, consisting,or consisting essentially of of the phosphorus ligand dppf (L1, Table 2)and the palladium metal compound palladium acetate (M1, Table 3). Inanother embodiment, the organic base is Cy₂NMe.

In a further embodiment, the C₁₋₆alcoholic solvent is methanol.

A compound of formula (1e) may be treated with methylamine; in a proticor aprotic solvent such as THF, DMF, DMA, ethanol, or a mixture thereof;at a temperature of about 0° C. to about 60° C.; to yield thecorresponding compound (X).

In an embodiment, methylamine is added as a THF solution.

In another embodiment, methylamine is added as a solution in MeOH.

In another embodiment, methylamine is added in its gaseous state.

Direct Conversion of Compound (VII) to Compound (X)

(i) Compound (VII) may be converted directly to compound (X) by reactingcompound (VII) in the presence of molybdenum hexacarbonyl; optionally inthe presence of one or more reagents such as norbornadiene,tetrabutylammonium bromide, or a base selected from triethylamine orDABCO; in an organic solvent selected from diglyme, dioxane,butyronitrile, propionitrile, or the like; followed by the addition ofmethylamine; at a temperature of from about 60° C. to about 140° C.; toyield the corresponding compound (X).

In one embodiment, the reagents norbornadiene, tetrabutylammoniumbromide, and DABCO are present.

In another embodiment, the organic solvent is butyronitrile or diglyme.

(ii) Alternatively, compound (VII) may be reacted under suitableaminocarbonylation conditions; under a carbon monoxide atmosphere; inthe presence of a palladium catalyst; in the presence of one or morephosphorus ligands; in the presence of a base selected from DIPEA,K₂CO₃, K₃PO₄, Cy₂NMe, or excess methylamine; in the presence ofmethylamine; at a temperature of from about room temperature to about100° C.; to yield the corresponding compound (X).

It has been found that a variety of palladium catalysts and phosphorusligands are suitable for this transformation. In an embodiment, thepalladium catalyst is either a pre-formed palladium catalyst or apalladium-ligand catalyst complex that is formed hi situ.

When the palladium catalyst is a pre-formed palladium catalyst, it isselected from CAT1 to CAT5, shown in Table 1 (above), and may be usedfor the preparation of compound (X).

In another embodiment, one or more phosphorus ligands selected from L1to L17, shown in Table 2 (above), may be used in combination with eithera pre-formed palladium catalyst (Table 1) or a palladium metal compound(Table 3), for the preparation of compound (X).

In another embodiment, a palladium metal compound selected from M1 or M2(Table 3, above) may be used, in combination with one or more phosphorusligands selected from L1 to L17 (Table 2), for the above-describedaminocarbonylation reaction.

Table 5 describes certain reaction conditions (G1 to G7) for theconversion of compound (VII) to Compound (X).

TABLE 5 Conditions for Aminocarbonylation of Compound (VII) to Compound(X) Metal/Cat. Precursor Ligand Base Conv. [%] Yield G1 Pd(P(tBu₃)₂ —DIPEA 100 95 G2 Pd(OAc)₂ L10 Cy₂NMe 100 93.9 G3 Pd(OAc)₂ L16 Cy₂NMe 10093.1 G4 [Pd(OMs)BA)]₂ L10 Cy₂NMe 100 91.8 G5 [Pd(OMs)BA)]₂ L16 Cy₂NMe100 88.5 G6 Pd(OAc)₂ L16 K₃PO₄ 100 83.7 G7 Pd(OAc)₂ L17 Cy₂NMe 95.1 83.5

In one embodiment, the palladium catalyst is Pd(P(tBu₃)₂ (CAT3, Table1), and the organic base is 1.2 equivalents of DIPEA.

In another embodiment, the palladium catalyst is comprised, consistingor consisting essentially of the phosphorus ligand L10 (Table 2) and thepalladium metal compound Pd(OAc)₂ (M1, Table 3). In a furtherembodiment, the base is Cy₂NMe.

In one embodiment, methylamine is added as a solution in a protic oraprotic solvent.

In another embodiment, methylamine is added as a THF solution.

In another embodiment, methylamine is added in its gaseous state.

In another embodiment, methylamine is added as a solution in methanol.

In yet another embodiment, methylamine is added as its methyl ammoniumhydrochloride salt.

In another embodiment, the organic solvent is THF.

One skilled in the art will further recognize that the reaction orprocess step(s) as herein described (or claimed) are allowed to proceedfor a sufficient period of time, at a suitable temperature or range oftemperatures, until the reaction is complete, as determined by anymethod known to one skilled in the art, for example, chromatography(e.g. HPLC, TLC, etc.). In this context a “completed reaction or processstep” means that the reaction mixture contains a decreased amount of thestarting material(s)/reagent(s) and an increased amount of the desiredproduct(s), as compared to the amounts of each present at the beginningof the reaction.

SPECIFIC EXAMPLES

The following Examples are set forth to aid in the understanding of theinvention, and are not intended and should not be construed to limit inany way the invention set forth in the claims which follow thereafter.

In the Examples that follow, some synthesis products are listed ashaving been isolated as a residue. It will be understood by one ofordinary skill in the art that the term “residue” does not limit thephysical state in which the product was isolated and may include, forexample, a solid, an oil, a foam, a gum, a syrup, and the like.

Example 1

Step A. Preparation of Compound II.

A vessel was charged with 19 g of compound (I), 5 g of triethylaminehydrobromide, 49 g of xylenes and 67 g DMF. A solution of 26 g ofphosphorous oxybromide in 16 g of xylene was dosed into the reactionmixture. The reaction mixture was heated to 100° C. for 3 h. The mixturewas then cooled to 70° C. To this mixture was added 75 g of a solutionof NaOH (10M). After phase separation at room temperature, the organiclayer was washed with a 84 g of an aqueous solution of NaOH (10M)followed by 84 g of an aqueous solution of NaCl (25%). The organic phasewas carried forward into the next step without further purification.Isolation by crystallization from heptane was performed forcharacterization purposes of compound (H). ¹H NMR (300 MHz, CDCl₃) δ9.36, 8.75.

Step B. Preparation of Compound (III).

To the previous solution of compound (II) in xylenes was added 8.7 g ofsodium cyanide and 6.8 g of copper (I) iodide and 45 g of butyronitrile.The mixture was heated to 120° C. for 20 h. The reaction mixture wascooled, washed twice with an aqueous solution of sodium carbonate (10%).The organic phase was carried forward into the next step. Isolation wasperformed for characterization purposes of compound (III). ¹H NMR (300MHz, DMSO-d₆) δ 149.3, 145.4, 133.9, 131.9, 130.1, 119.5, 114.0.

Step C. Preparation of Compound (IV).

Preparation of Modified Catalyst Slurry.

In a 20 mL beaker glass 0.156 g (0.129 mL, 50% w/w) of H₃PO₂ was addedto a slurry of 1.00 g 5% Pt/C catalyst F101 R/W (from Evonik AG,contains ˜60% water) and 4.0 mL of deionized water. After 15 minuteswhile stirring with a magnetic stirring bar, 58 mg of NH₄VO₃ was addedand the slurry was again stirred for 15 minutes.

Hydrogenation.

A 100 mL autoclave was charged with a solution of 10.0 g of compound(III) (46.1 mmol) in 26.7 mL of xylenes and 13.3 mL of butyronitrile. Tothis solution, the modified catalyst slurry was added with the aid of 2mL of deionized water. The autoclave was closed, then inertized bypressurizing 3 times with nitrogen to 10 bar and 3 times hydrogen to 10bar. The reactor pressure was set to 5.0 bar hydrogen, stirring wasstarted (hollow shaft turbine stirrer, 1200 rpm) and the mixture heatedup to 70° C. within 50 min. As soon as 70° C. was reached, the hydrogenuptake ceased. After stirring for another 40 min, the heating wasstopped and the autoclave was allowed to cooling. The slurry wasfiltered through a fiberglass filter and washed in portions using 40 mLof xylenes at 20-23° C. Compound (IV) was crystallized from the solutionupon distillation of the butyronitrile solvent. ¹H NMR (300 MHz,DMSO-d₆) δ 8.20 (d, J=2.4 Hz, 1H), 7.31 (d, J=2.6 Hz, 1H), 7.04 (s, NH).

Step D. Preparation of Compound (VII).

To a reactor containing compound (VI) (25 g) and compound (IV) (14 g)was added 1-(2-oxopyridine-1-carbothioyl)pyridin-2-one (18 g) andtoluene (316 mL). The reaction mixture was stirred and heated to 100° C.for 20 h. A solvent switch from toluene to DMA (8 L/kg finalcomposition) was performed, then EtOH (400 mL) was added. The mixturewas then heated to 70° C. before addition of HCl (2 M, 160 mL). Afterstirring for 2 h, the reaction was cooled down to 0° C. The precipitatewas collected by filtration, rinsed with EtOH/H₂O (100 mL, 1:1), anddried to give compound (VII) (24 g, 63%). ¹H NMR (300 MHz, CDCl₃) δ 9.09(d, J=2.1 Hz, 1H), 8.35 (d, J=2.1 Hz, 1H), 8.01 (dd, J=8.3, 6.8 Hz, 1H),7.07 (dd, J=7.9, 2.3 Hz, 1H), 6.94 (dd, JJ=8.0, 2.0 Hz, 1H), 2.72 (m,2H), 2.58 (m, 2H), 2.30 (m, 1H), 1.74 (m, 1H).

Step E. Preparation of Compound (VIII).

A reactor was charged with a solution of 5 g of compound (VII) in 50 mLof anhydrous THF and stirring begun. The reaction solution was cooled toan internal temperature of 0° C. A solution of n-pentylmagnesiumchloride (1 eq) was added slowly to maintain a reaction temperature of0° C. After 30 min, carbon dioxide gas was added into the stirredreaction mixture. Upon consumption of the starting material, thereaction mixture was added to a solution of aqueous acetic acid (10%) toyield compound (VIII) (75%). ¹H NMR (300 MHz, CDCl₃) δ 9.11 (d, 1H),8.37 (d, 1H), 8.20 (m, 1H), 7.25 (m, 2H), 5.30 (s, 1H), 2.75 (m, 2H),2.61 (m, 2H), 2.31 (m, 1H), 1.74 (m, 1H).

Step F. Preparation of Compound (IX).

Method A.

A pressure reactor was charged with Compound (VII) (1 g), palladiumacetate (10 mol %), dppf (10 mol %), and diisopropylamine (1 eq) andmethanol (10 mL). The reaction was placed under carbon monoxide (4 bar)and heated for 4 h at 60° C. The reaction was allowed to cool to ambienttemperature, diluted with dichloromethane (5 mL), then washed with a 3%cysteine aqueous solution. The organic layer was separated,concentrated, and dried to yield compound (IX) (85%). ¹H NMR (300 MHz,CDCl₃) δ 9.10 (d, J=1.9 Hz, 1H), 8.36 (d, J=1.9 Hz, 1H), 8.20 (m, 1H),7.20 (m, 2H), 4.00 (s, 3H), 2.75 (m, 2H), 2.58 (m, 2H), 2.30 (m, 1H),1.76 (m, 1H); ¹³C NMR (CDCl₃, JMOD) δ 179.6, 174.2, 163.3, 159.2, 153.4(ArH), 140.9, 135.5 (ArH), 132.9 (ArH), 1289, 126.5 (ArH). 118.9 (ArH),114.2, 67.7, 52.6, 31.1, 13.4.

Method B.

A reactor was charged with 2.5 g of compound (VII) in 25 mL2-methyl-THF. The mixture was stirred under Argon at −15° C. A solutionof n-pentylmagnesium chloride in THF (2M, 2.4 mL) was dosed over 1 h.After 15 min of stirring, methyl chloroformate (1.1 eq, 0.40 mL) wasadded dropwise and the temperature was then allowed to warm to 15° C.The reaction was quenched with a solution of 10% AcOH in water (20 mL).After phase separation, the organic layer was washed with water and thenconcentrated to yield compound (IX) in 77% yield.

Method C.

A reactor was charged with 2 g of compound (VII) in 20 mL of THF. Themixture was stirred under Argon at 50° C. A solution ofisopropylmagnesium chloride lithium chloride complex in THF (1.3M, 3.4mL) was dosed over 10 min. After 5 min of stirring, methyl cyanoformate(1.25 eq, 0.37 mL) was added dropwise and the temperature was then allowto warm to 15° C. The reaction was quenched with a solution of 10% AcOHin water (20 mL). After the phase separation, the organic layer waswashed with water and then concentrated to yield compound (IX) in 75%yield.

Step G. Preparation of Compound (X).

A reactor was charged with compound (IX) (0.3 g) and a solution ofmethylamine in ethanol (10 eq) and stirring begun. The reaction wasstirred at ambient temperature. Upon consumption of compound (IX), thereaction was concentrated, re-dissolved in toluene, and washed withaqueous HCl (2M) until all base was neutralized. The toluene phase wasthen concentrated to give compound (X) (80%). ¹H NMR (300 MHz, DMSO) δ9.22 (d, J=1.9 Hz, 1H), 8.76 (d, J=1.9 Hz, 1H), 8.50 (d, J=4.5 Hz, 1H),7.84 (t, 1H), 7.48 (dd, J=10.5, 1.8 Hz, 1H), 7.39 (dd, J=8.2, 1.8 Hz,1H), 4.00 (s, 3H), 2.75 (m, 2H), 2.58 (m, 2H), 2.30 (m, 1H), 1.76 (m,1H).

Example 2

Method A.

In a 10 mL test tube, compound (VII) (0.3 g, 0.55 mmol), molybdenumhexacarbonyl (0.145 g, 0.55 mmol), norbomadiene (0.05 g, 0.545 mmol),tetrabutylammonium bromide (0.177 g, 0.55 mmol) and DABCO (0.185 g, 1.65mmol) were charged under nitrogen, followed by 3 mL of diglyme. Themixture was heated with stirring under a nitrogen atmosphere to 140° C.Methylamine hydrochloride (0.05 g, 0.61 mmol) was added, and the mixturewas stirred at 140° C. for 1 h to yield compound (X) (13%).

Method B.

In a 10 mL test tube, compound (VII) (0.3 g, 0.55 mmol), molybdenumhexacarbonyl (0.145 g, 0.55 mmol), norbomadiene (0.05 g, 0.545 mmol),tetrabutylammonium bromide (0.177 g, 0.55 mmol) and DABCO (0.185 g, 1.65mmol) were charged under nitrogen, followed by 3 mL of butyronitrile.The mixture was heated with stirring under a nitrogen atmosphere to 140°C. Methylamine hydrochloride (0.05 g, 0.61 mmol) was added in 3 portionsover 30 min, and the mixture was stirred at 118° C. for 1 h to yieldcompound (X) (43%).

Method C.

A 30 mg (0.059 mmol) portion of Pd(t-Bu₃P)₂ was placed in a 10 mLSchlenk flask, which was subsequently set under an inert atmosphere(Argon). Then 3 mL of degassed THF was added and the solution stirredfor 5 min at ambient temperature. In a second 20 mL Schlenk flask, 0.8 gof compound (VII) (1.464 mmol) was inertized and 4.3 mL degassed THF,3.7 mL (7.32 mmol, 2M in THF) N-methylamine, and 0.37 mLdicyclohexylmethylamine (1.75 mmol) were added. Both the substratesolution and the catalyst solution were transferred via cannula into the50 mL autoclave, which was previously set under an inert atmosphere ofArgon. The reactor was sealed and purged with Argon, and finally theArgon was replaced by 5 bar CO (three purge cycles). The reaction wasstirred and heated to 60° C. for 2 h.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

1. A process for preparing compound 1c:

the method comprising converting compound VII to compound 1c:


2. The process of claim 1, comprising: reacting compound VII with anorganomagnesium halide; in the presence or absence of a lithium halide;and adding carbon dioxide gas; in an aprotic organic solvent; at atemperature of about 0° C. to yield compound 1c.
 3. The process of claim1, comprising reacting compound VII under a carbon monoxide atmosphere;in the presence of a palladium catalyst; in the presence of one or morephosphorus ligands; in the presence of water; in a solvent; at atemperature of about 0° C. to about 100° C. to yield the compound 1c.